Loss of TAK1 increases cell traction force in a ROS-dependent manner to drive epithelial-mesenchymal transition of cancer cells.
Loss of TAK1 increases cell traction force in a ROS-dependent manner to drive epithelial-mesenchymal transition of cancer cells.
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DOI：
10.1038/cddis.2013.339
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发表时间：
2013-10-10
影响因子：
9
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上皮-间充质转化是肿瘤发生发展过程中的重要环节，而转化生长因子β-SMAD信号通路在多种肿瘤类型中作为上皮-间充质转化的诱导者已被广泛认识。然而，非典型性转化生长因子β-Tak1信号在子宫内膜癌中的作用尚不清楚。在这里，我们表明，TAK1缺乏促使转移性皮肤鳞状细胞癌更早进入EMT，这是以细胞ROS水平升高为条件的。在浸润性鳞癌活检组织中，TAK1的表达持续降低。来自TAK1缺陷细胞的肿瘤也表现出明显的侵袭性形态。TAK1基因缺失的癌细胞具有更多的间质形态，其特征是有更多的局灶性粘连，表面整合素α5β1和活性RAC1的表达增加。值得注意的是，这些突变的细胞施加了增加的细胞牵引力，这是转化生长因子β1诱导的子宫内皮细胞转化过程中的早期细胞反应。与对照癌细胞相比，与间充质表型相关的转录因子ZEB1和Snail的mRNA水平也在TAK1缺陷的癌细胞中上调。我们进一步证明，TAK1通过依赖于RhoA的氧化还原下调RhoA来调节rac1和RhoA GTP酶的活性，这涉及到低分子蛋白酪氨酸磷酸酶的氧化修饰。重要的是，用Rho相关蛋白激酶的选择性抑制剂Y27632和抗氧化剂N-乙酰半胱氨酸治疗TAK1缺陷的癌细胞分别增强和阻碍EMT。我们的研究结果表明，转化生长因子β-Tak1和转化生长因子β-sMAD信号通路激活的失衡在转化生长因子β-1诱导的子宫内膜间质转化中起着关键作用。因此，转移性癌细胞中TAK1缺乏增加了整合素：RAC诱导的ROS，它通过LMW-PTP负调控Rho来加速EMT。
Epithelial–mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ–SMAD signaling pathway as an inductor of EMT in many tumor types is well recognized. However, the role of non-canonical TGFβ–TAK1 signaling in EMT remains unclear. Herein, we show that TAK1 deficiency drives metastatic skin squamous cell carcinoma earlier into EMT that is conditional on the elevated cellular ROS level. The expression of TAK1 is consistently reduced in invasive squamous cell carcinoma biopsies. Tumors derived from TAK1-deficient cells also exhibited pronounced invasive morphology. TAK1-deficient cancer cells adopt a more mesenchymal morphology characterized by higher number of focal adhesions, increase surface expression of integrin α5β1 and active Rac1. Notably, these mutant cells exert an increased cell traction force, an early cellular response during TGFβ1-induced EMT. The mRNA level of ZEB1 and SNAIL, transcription factors associated with mesenchymal phenotype is also upregulated in TAK1-deficient cancer cells compared with control cancer cells. We further show that TAK1 modulates Rac1 and RhoA GTPases activities via a redox-dependent downregulation of RhoA by Rac1, which involves the oxidative modification of low-molecular weight protein tyrosine phosphatase. Importantly, the treatment of TAK1-deficient cancer cells with Y27632, a selective inhibitor of Rho-associated protein kinase and antioxidant N-acetylcysteine augment and hinders EMT, respectively. Our findings suggest that a dysregulated balance in the activation of TGFβ–TAK1 and TGFβ–SMAD pathways is pivotal for TGFβ1-induced EMT. Thus, TAK1 deficiency in metastatic cancer cells increases integrin:Rac-induced ROS, which negatively regulated Rho by LMW-PTP to accelerate EMT.